CNSPulse

COMBINED KETAMINE AND COGNITIVE BEHAVIORAL THERAPY: LEVERAGING METAPLASTICITY TO ENHANCE OUTCOMES

Songjun Li — Morgan Hardy2, Samuel Wilkinson2 1Yale, Yale University School of Medicine Songjun Li, Yale

2026 ASCP Annual Meeting

Background and

Purpose

Ketamine and intranasal esketamine have transformed the landscape of Treatment-Resistant Depression (TRD) by offering rapid and robust symptom relief. However, a critical limitation remains: durability. The antidepressant effects of NMDA receptor antagonists are often transient, leading to high relapse rates upon discontinuation and necessitating indefinite, resource-intensive maintenance schedules, which miss a fundamental biological opportunity. Ketamine induces not only immediate synaptic plasticity (synaptogenesis) but also metaplasticity, a transient increase in the brain’s capacity for future rewiring. This creates a critical post-treatment window (approximately 12–72 hours post-dosing) during which neural circuits are hypersensitive to reshaping. Methodology: We conducted a systematic review of the literature through December 2025 to evaluate the theoretical rationale and empirical efficacy of pairing ketamine with cognitivebehavioral interventions. We specifically distinguished this mechanistically grounded approach from Ketamine-Assisted Psychotherapy, focusing instead on structured cognitive retraining delivered during the post-acute consolidation window rather than during the acute dissociative state.

Results

Our review identified a consistent signal across multiple trials, suggesting synergistic effects between ketamine and cognitive interventions. Early open-label data and subsequent randomized controlled trials (e.g., Wilkinson et al., 2021) demonstrate that initiating CBT during the ketamine course significantly extends time-to-relapse compared to standard care. Furthermore, large-scale studies utilizing automated digital cognitive training (e.g., Price et al., 2022) delivered post-infusion have shown statistical superiority in sustaining antidepressant effects, validating the concept of leveraging the “plasticity window”. Based on these findings, we propose a novel model for clinical workflow: an Induction phase focused on rapid symptom reduction, followed by a Consolidation phase where high-intensity CBT is introduced to reshape adaptive circuits during peak metaplasticity, transitioning to a Maintenance phase focused on skill reinforcement. Conclusion and Importance: This review highlights a critical opportunity to shift the ketamine/esketamine paradigm from symptom reduction to durable circuit rewiring. We also propose that prescription digital therapeutics (PDTs) offer a pragmatic solution, enabling the precise delivery of behavioral therapies during the optimal post-treatment “plasticity window” without overburdening clinical workforce capacity. Future studies should evaluate this model to determine if combinatorial, digital-and-pharmacotherapeutic neuroplasticity can successfully reduce pharmacologic maintenance, ultimately establishing a new standard of multimodal care for treatment-resistant depression.

Learning Objective 1: Describe the theoretical framework of metaplasticity induced by NMDA receptor antagonists and how it creates a time-sensitive window for cognitive retraining.

Learning Objective 2: Identify a novel, three-phase clinical workflow that integrates scalable digital therapeutics to extend the durability of interventional depression treatments.

References

  • Wilkinson ST, Rhee TG, Joormann J, et al. Cognitive Behavioral Therapy to Sustain the Antidepressant Effects of Ketamine in Treatment-Resistant Depression: A Randomized Clinical Trial. Psychother Psychosom. 2021;90(5):318–327. - Price RB, Spotts C, Panny B, et al. A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial. Am J Psychiatry. 2022;179(12):959–968.